Synthesis of Isoquinoline Alkaloids

Skiles and Cava have investigated the alkylation method of isoquinoline Reissert compounds (76), performing a comparative study on the alkylation of 

Potassium hydroxide with benzene in the presence of dicyclohexyl-18-crown-6 

50% aqueous sodium hydroxide with benzene or acetonitrile in the presence of phase-transfer catalyst (cetrimonium bromide) 

According to measured yields, conditions B and C have been found to be much more advantageous than method A (see Table I). 

Cularine (67) and related alkaloids constitute a small group of 1-benzyliso-quinoline-related alkaloids, which are distinguished from the main group by 

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The intramolecular Diels-Alder reaction of 78 was investigated during the synthesis of isoquinoline alkaloids [65ij. No reaction occurred when solid-phase conditions were used (Florosil in DCM and CaCli) or when a variety of Lewis acids were employed (SnCU, BF3, RAICI2, Ti(z — Pr)4-TiCl4). A 56 % yield of 79 was obtained by carrying out the cycloaddition in toluene in a sealed tube at 200 °C. jS-CD catalysis in water under milder conditions (Equation 4.11) improved the conversion to 84 %. 

Intramolecular Diels-Alder reaction of substituted fiirans has been investigated as a route to the synthesis of isoquinoline alkaloids. Tetrahydroisoquinoline 81 was prepared from furan 80 in 40% yield <95JCS(P1)2393>. 

Isoquinoline alkaloids. The regioselective allylation of N-acyl heterocycles (13, 10) can be used for synthesis of isoquinoline alkaloids. Thus simultaneous reaction of the dihydroisoquinoline (1) with a diunsaturated acyl chloride (2) and allyltributyltin affords the 1,2-adduct (3), which undergoes a Diels-Alder cyclization... 

Somewhat more effective catalysts are obtained by replacing BINAP with TolBINAP, which is 2,2 -bis(di-p-tolylphosphino)-l,l -binaphthyl.4 The presently preferred catalysts are complexes of Ru(OCOCF3)2 with (R)- or (S)-TolBINAP, obtained by treatment of Ru(OAc)2TolBINAP with 2 equiv. of trifluoroacetic acid. Such catalysts promote hydrogenation of typical enamides in 98% ee and 98% yield. This reaction can be used to provide asymmetric synthesis of isoquinoline alkaloids as well as of morphinans used as substitutes for morphine. 

B. Reaction of Reissert Compounds Synthesis of Isoquinoline Alkaloids... 

The chemistry of Reissert compounds has been the subject of numerous general reviews (3-10). In 1973 Popp gave a summary on the use of Reissert compounds in the synthesis of isoquinoline alkaloids and related compounds (7). We now wish to summarize new results that have appeared from 1973 to the end of 1985 for the application of Reissert compounds in the synthesis of isoquinoline as well as indole alkaloids. 

Isoquinoline Synthesis. Olefins that contain certain neutral donor functionalities are also effectively hydrogenated. Investigation of the enan-tioselective hydrogenation of enamide substrates has resulted in a general procedure for the asymmetric synthesis of isoquinoline alkaloids. 

Although a number of other effective synthetic methodologies have been developed for the synthesis of isoquinoline alkaloids (1,2), there still remain quite a number of alkaloids which have not been synthesized, even by using newer methods. Improvement of existing methodologies and the introduction of new ones should provide more efficient and convenient syntheses of alkaloids. 

Several reviews on enamide photocyclization (11-13) and photochemical synthesis of isoquinoline alkaloids (14) have been published. 

Kametani<23) in 1977 reviewed the total synthesis of isoquinoline alkaloids, including alkaloids of the morphine series. 

Enantioselective hydrogenation of certain a- and 3-(acylamino)acrylic acids or esters in alcohols under 1-4 atm H2 affords the protected a- and 3-amino acids, respectively (eqs eq 3 and eq 4). Reaction of N-acylated 1-alkylidene-1,2,3,4-tetrahydroisoquinolines provides the IR- or 15-alkylated products. This method allows a general asymmetric synthesis of isoquinoline alkaloids (eq 5). ... 

Scheme 25. General asymmetric synthesis of isoquinoline alkaloids.

Rozwadowska, M. D. Recent progress in the enantioselective synthesis of isoquinoline alkaloids. Heterocycles 1994, 39, 903-931. 

The chemistry of Reissert compounds, for example, N-acyldihydroquin-aldonitriles (1) and Af-acyldihydroisoquinaldonitriles (2), was the subject of a review in an earlier volume of this series. The application of Reissert compounds to the synthesis of isoquinoline alkaloids and related compounds... 

Most work has been in the isoquinoline area, principally because of the usefulness of isoquinoline Reissert compounds in the synthesis of isoquinoline alkaloids. Aside from 5-chloro- and 3-acetylaminomethylquinoline and a few halo, methyl, and carbomethoxyisoquinolines, all the substituted quinoline or isoquinoline Reissert compounds have involved oxygen-type functions in one or more of positions 4-, 5-, 6-, 7-, and 8- of the isoquinoline... 

A review by Chrzanowska and Rozwadowska <04CRV3341> summarizes two key strategies for the synthesis of isoquinoline alkaloids stereochemically modified traditional methods and recent advances using the Cl-Ca connectivity approach. Literature from late 1993 to late 2003 is covered in this review. 

One of the most important fields of application of the Pschorr reaction is the synthesis of isoquinoline alkaloids. The syntheses of thalicsimidine [72] (Scheme 46) and aporphine [73] are typical examples. 

More recently, the preparative value of VOCl3 and VOF3-TFA in chemical oxidation has been demonstrated (see Section III, on the pro-aporphine and promorphinane alkaloids) (415,462). Some other authors used the purified enzyme horseradish peroxidase (463). By this method the aporphine base (besides the quaternary dibenzopyrrocoline) is readily obtained from (S)-( + )-laudanosoline hydrobromide or from (/ )-(—)-laudanosoline methiodide with retention of the absolute configuration. The synthesis of 6a,7-dehydroaporphine bases was also carried out by making use of the benzyne reaction (439). Reduction of these substances affords the corresponding aporphine bases (439). The synthesis of isoquinoline alkaloids by lead tetraacetate oxidation was reviewed by Umezawa and Hoshino (343). 

The partial ether cleavage of methoxy- and methylenedioxy-substituted isoquinoline alkaloids has been reviewed in a new journal. Additional reviews concerning the use of Reissert compounds in the total synthesis of isoquinoline alkaloids and related compounds, electro-oxidation and isoquinoline alkaloid biosynthesis, and the synthesis of isoquinoline alkaloids by a systematic design have appeared in early issues of the same journal. The chemotaxonomy of alkaloids, together with distribution within plants, biosynthesis, structural classification, and physiological activity, has been treated in a monograph. ... 

The usefulness of benzocyclobutenyl derivatives for the synthesis of isoquinoline alkaloids (see Vols. 2—4 of these Reports) has been extended to the preparation of the protoberberine bases (Schemes 9 and 10). In one case (Scheme 9), compound (155) was thermolysed to afford the protoberberinium salt (157), the reaction plausibly proceeding via the ortho-quinonoid intermediate (156), which then undergoes electrocyclization and dehydrogenation to give the product. Reduction of (157) then provided the protoberberine (158 R = H, R = R = Me). This route was used for the synthesis of (+ )-discretine (158 R = H,... 

The conjugate base of (5,5j-bis(4-isopropyloxazolin-2-yl)methane 39 complexes to illylzinc halides and then delivers the allyl group to cyclic aldimines stereoselectively. This method is applicable to the synthesis of isoquinoline alkaloids. 

Alcoholics and morphine-takers use, directly or indirectly, the Pictet-Spengler reaction for the synthesis of isoquinoline alkaloids. [84] In the liver, with the production of the corresponding redox equivalents of NADH, ethanol is oxidised via acetaldehyde to acetic acid. The kinetics of the reactions is such that for an extended period during the alcohol degradation, there exists a quasl-statlonary concentration of 1 xg/ml acetaldehyde In the blood. Acetaldehyde reacts with the catecholamines to produce tet-rahydrolsoqulnollnes. These Interact competitively at the catecholamine receptors, and thereby disturb the equilibrium of the vegetative nervous system, which in the course of time leads to addiction. 

Chrzanowska M, Rozwadowska MD (2004) Asymmetric Synthesis of Isoquinoline Alkaloids. Chem Rev 104 3341... 

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